Atypical parathyroid adenoma with severe bone manifestations in early adolescence

Abstract

This is a case of primary hyperparathyroidism in a female teenager with multiple fractures and severe bone manifestations. The histopathology revealed atypical parathyroid adenoma, an exceedingly rare form of hyperparathyroidism; its main differential diagnosis is parathyroid carcinoma, as it shares both clinical and histological characteristics with it, in addition to its still uncertain malignant potential.

Background

Primary hyperparathyroidism (PHPT) results from the autonomous and excessive secretion of parathyroid hormone (PTH) from one or more of these glands, producing hypercalcaemia, associated with elevated or inappropriately normal levels of PTH.^1–7 In children, it is considered a rare condition, the majority of children (85%) being symptomatic, with more severe and diffuse bone involvement and milder renal manifestations compared with adults.² Atypical parathyroid adenoma (APA) is a rare aetiology (1.2–1.3%) of PHPT^{7 8} and the diagnosis is histopathological. It has significant relevance due to its uncertain malignant potential, exhibiting both macro- and microscopic high-risk characteristics, but which do not fully meet the criteria for parathyroid carcinoma (PC).^{8 9}

We illustrate a rare presentation of PHPT in a young patient admitted with significant wasting syndrome and extremely elevated levels of PTH and calcium, leading to severe bone manifestations of PHPT.

Case presentation

The case involved a female in early adolescence, previously healthy, who started with bone pain which affected her feet and progressed to long bones, ribs, and vertebrae. The pain was continuous and worsened with movement. The intensity of the pain had gradually worsened, associated with bone deformities and bone tumour growth in the right clavicle and knees. Two years later, she was admitted to the emergency room of our hospital with a spontaneous fracture of the left femur.

The patient reported loss of appetite, polyuria, polydipsia, and dyspepsia, leading to a loss of 56% of her previous weight and progressive weakness, impacting her daily activities. A few months before her evaluation, she was no longer able to walk. On examination, she was in a weakened general condition, bedridden, exhausted and pale. The anthropometric assessment showed short stature (Z score −2.9) and malnutrition, with a body mass index of 15 kg/m² and complete pubertal development. She presented deformities in the rib cage, with soft and misshapen bones, bone tumours at the distal end of the right clavicle and first left costal arch, with increased volume and local temperature, without hyperaemia. She also had significant scoliosis and increased bone volume and local temperature in the left knee. In the left cervical region, a fibroelastic, mobile nodule, measuring approximately 2 cm, was palpable (figure 1).

Figure 1.

Clinical Images of the patient. (A) Brown tumours on the knees. (B) Extensive cervical nodule on the left and brown tumours on the distal right collarbone and on the proximal left collarbone.

Biochemical tests (table 1) revealed PTH-related hypercalcaemia, with calcium 4.19 mmol/L (reference values 2.1–2.52 mmol/L), PTH 4059 pg/mL (62 times higher; 15–65 pg/mL) and low levels of magnesium 0.45 mmol/L (0.74–0.99 mmol/L), vitamin D 16.6 ng/mL (>20 ng/mL) and potassium 3.3 mEq/L (3.6–5 mEq/L). The albumin level was 40 g/L (34–50 g/L), phosphorus 1.16 mmol/L (0.81–1.58 mmol/L), creatinine 45.97 µmol/L (53.04–88.4 µmol/L), 24 hour urinary calcium of 253 mg/day (8 mg/kg body weight; 100–300 mg/day), and alkaline phosphatase 6600 U/L (75–390 U/L), which strongly suggested PHPT. The electrocardiogram demonstrated sinus tachycardia, without changes in the QT interval.

Table 1.

Laboratory findings preoperatively (pre-op) and postoperatively (post-op)

	Adm	ZA	HBS 48 hours	Pre-op	Immediate post-op	72 hours post-op	6 months post-op	Reference values
Serum calcium (mmol/L)	4.19	3.67	1.65	2.3	1.89	1.92	2.36	2.1–2.52
Parathyroid hormone (pg/mL)	>3000	4059	–	–	269.7	273.5	60.26	15–65
Albumin (g/L)	40	39	25	33.6	30	29	43.7	34–50

Adm, admission; HBS 48 hours, hungry bone syndrome 48 hours after ZA; ZA, zoledronic acid.

Investigations

Skull, hand, and leg X-rays show bone resorption in the skullcap, distal phalanges, tibia, and fibula, in addition to leg curvature deformities (figures 2–4). Non-contrast thorax CT demonstrated a cervical nodule on the left thyroid lobe, signs of subchondral resorption at the distal ends of the clavicle, and brown tumour on the first costal arch (figure 5). The abdominal tomography showed a renal microcalculus on the left and a small pancreas with multiple calcifications, although the patient did not present steatorrhoea or symptoms of nephrolithiasis (figure 6). Bone scintigraphy demonstrated a diffuse osteogenic reaction in the cranial vault and focally in the left superior orbit, in the sacroiliac joints and in the sacrum, in addition to a volumetric increase in the mandible; lesions with an osteolytic appearance were evident on the left femur, destroconvex thoracic scoliosis and a sinister convex lumbar scoliosis. Ultrasound of the cervical region showed a hypoechoic, solid, well-vascularised nodule, measuring 2.6 cm, well-defined, next to the lower pole of the left thyroid lobe, and confirmed by cervical tomography, which revealed a homogeneous hypoattenuating nodular image with well-defined contours in the same location. Sestamibi scintigraphy associated with tomographic images showed an abnormal accumulation of the radiopharmaceutical in a focal area near the lower pole of the left thyroid lobe, confirming a hyperfunctioning nodule (figure 7).

Figure 2.

Skull X-ray shows bone resorption in the skullcap.

Figure 3.

Hand X-ray shows bone resorption of the distal phalanges.

Figure 4.

Tibia and fibula X-ray demonstrating curvature deformities and diffuse bone rarefaction.

Figure 5.

Axial image of non-contrast CT of thorax. (A) Cervical nodule on the left thyroid lobe. (B) Signs of subchondral resorption at the distal ends of the clavicle. (C) Brown tumour on first costal arch.

Figure 6.

Axial images of non-contrast CT of abdomen. (A) Left kidney calcification. (B) Diffuse pancreatic calcifications.

Figure 7.

Sestamibi scintigraphy shows an abnormal accumulation of the radiopharmaceutical in a focal area near the lower pole of the left thyroid lobe, confirming a hyperfunctioning nodule.

Differential diagnosis

Considering the consumptive condition, palpable neck mass, severe hypercalcaemia and exceedingly high PTH levels, PC was suspected and surgery was indicated.

Treatment

Radical surgery was indicated due to the high probability of malignancy. In the preoperative period the patient received calcitriol and a dose of zoledronic acid (ZA) to prevent postoperative complications. She developed bone hungry bone syndrome after ZA and required calcium and phosphorus replacement before the surgery.

After stabilisation of fluid and electrolyte disorders, she underwent isthmectomy, left lobectomy, parathyroidectomy and left cervical node dissection.

Outcome and follow-up

Although the entire clinical, laboratory and radiographic evolution was suggestive of PC, the histopathological analysis, after reviewing the slide, described a nodular tumour of considerably large size for a parathyroid tumour, with an organoid appearance, consisting of small islands grouped around a necrotic centre. The tumour was well delimited by a thick fibrotic capsule, in which there were exceedingly rare groups that infiltrated it, exceeding the external diameter of most cells, but did not transfix the capsule.

The nuclear pattern, coarsely granular, was very homogeneous. There was no nuclear atypia or mitotic activity. There were no vascular, perineural or neighbouring tissue invasion. Immunohistochemistry showed a low proliferative index, with the diagnostic impression being an APA. The patient recovered well after surgery, maintaining calcium, calcitriol and phosphorus supplementation. She showed improvement regarding pain within the first 30 days after surgery. Three months later, she began to walk again; 6 months after the surgery, her PTH had normalised, there was a progressive fall in alkaline phosphatase, and an improvement in bone deformities.

Discussion

This case report describes a young patient presenting with severe wasting syndrome and remarkably high levels of PTH and calcium, leading to acute bone manifestations of PHPT and suspected PC. PHPT is rare in childhood and adolescence, with an estimated prevalence of 2–5 per 100 000 children.¹⁰

Although in the paediatric age group PC is a rare aetiology of PHPT, distinguishing between benign and malignant parathyroid diseases is a challenge. Clinical suspicion is essential for appropriate management, despite the definitive diagnosis being made only through histopathological⁸ diagnostic confirmation of APA, which in the case reported here could only be performed after parathyroidectomy based on the recently updated WHO criteria.¹¹ APA, currently called atypical parathyroid tumour, presents histological characteristics similar to PC^{11 12}; however it does not have complete capsular invasion or presence of metastases.¹¹

In children and adolescents, there is a higher possibility of multiglandular and genetic syndromes associated with PHPT, as is the case with multiple endocrine neoplasia (MEN).⁹ The CDC73 germline mutation was the most common molecular abnormality in individuals with APA.¹³ Even though we excluded other endocrinopathies that could suggest MEN, due to resource constraints genetic analysis could not be done.

In children, most APAs are symptomatic at diagnosis, similar to our patient who presented with osteitis fibrosa cystica. Brown tumours are clinically difficult to diagnose, as they often mimic malignancy. It is likely that stimulating high bone growth in adolescents may contribute to a greater prevalence of bone manifestations in this age group.^{2 3} In our initial approach we found that the patient presented with severe consumptive syndrome, with short stature. The chronic and multisystemic involvement of the disease, with significant musculoskeletal and renal manifestations, contributed to the severe malnutrition.^{2 3 14}

In the paediatric population, renal involvement typically manifests as nephrolithiasis, having a positive correlation with hypercalciuria and a negative correlation with bone mineral density^{2 3} as reported.

The preoperative management for lowering serum calcium is mandatory before surgery.¹⁵ Initial therapy of severe hypercalcaemia includes the simultaneous administration of saline and bisphosphonates. These agents are the treatment of choice as they inhibit the osteoclasts’ activity which is the major mechanism responsible for severe hypercalcaemia. Severe hypocalcaemia, hypophosphataemia, and hypomagnesaemia (hungry bone syndrome) can develop, and the patients must be monitored carefully, as reported.¹⁵ When PC is suspected in patients with a hypercalcemic crisis, en bloc resection (resection of the surrounding capsule and concurrent hemithyroidectomy) is recommended.¹⁵

Remission of PHPT usually occurs over a period of 6 months after surgery and involves normalisation of blood calcium and PTH levels,¹³ and is closely related to complete tumour resection.⁸

The relevance of this case is the atypical presentation of hyperparathyroidism in an adolescent, with extremely high levels of calcium and PTH, leading to severe bone involvement, a clinical condition rarely reported.

We highlight the physiological bases of the more pronounced bone involvement in this age group, the challenge of adequate diagnosis and the importance of follow-up in cases such as this one, as the prognosis is still uncertain.

Learning points.

• Atypical parathyroid adenoma is a rare aetiology of primary hyperparathyroidism.

• In the paediatric population, bone manifestations are more severe.

• Its main differential diagnosis is parathyroid carcinoma.

• Although parathyroidectomy offers a cure, its malignant potential is still uncertain.

Ethics statements

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